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Radiation-induced alterations in immunogenicity of a murine pancreatic ductal adenocarcinoma cell line.
Scientific Reports ( IF 3.8 ) Pub Date : 2020-01-20 , DOI: 10.1038/s41598-020-57456-2
Philipp Schröter 1, 2, 3, 4 , Laura Hartmann 1, 5 , Wolfram Osen 1 , Daniel Baumann 6, 7 , Rienk Offringa 6, 7 , David Eisel 1, 5, 8 , Jürgen Debus 2, 3, 4 , Stefan B Eichmüller 1 , Stefan Rieken 2, 3, 4
Affiliation  

Pancreatic ductal adenocarcinoma (PDA) is highlighted by resistance to radiotherapy with the possible exception of hypofractionated irradiation. As single photon doses were reported to increase immunogenicity, we investigated dose-dependent irradiation effects on clonogenic survival, expression of immunologically relevant cell surface molecules and susceptibility to cytotoxic T cell (CTL) mediated killing using a murine PDA cell line. Clonogenicity decreased in a dose-responsive manner showing enhanced radioresistance at single photon doses below 5 Gy. Cell cycle analysis revealed a predominant G2/M arrest, being most pronounced 12 h after irradiation. Polyploidy increased in a dose- and time-dependent manner reaching a maximum frequency 60 h following irradiation with 10 Gy. Irradiation increased surface expression of MHC class I molecules and of immunological checkpoint molecules PDL-1 and CD73, especially at doses ≥ 5 Gy, but not of MHC class II molecules and CXCR4 receptors. Cytotoxicity assays revealed increased CTL lysis of PDA cells at doses ≥ 5 Gy. For the PDA cell line investigated, our data show for the first time that single photon doses ≥ 5 Gy effectively inhibit colony formation and induce a G2/M cell cycle arrest. Furthermore, expression levels of immunomodulatory cell surface molecules became altered possibly enhancing the susceptibility of tumour cells to CTL lysis.

中文翻译:


辐射诱导的小鼠胰腺导管腺癌细胞系免疫原性的改变。



胰腺导管腺癌(PDA)的突出特点是对放疗的抵抗,大分割放疗可能除外。据报道单光子剂量可增加免疫原性,我们使用鼠 PDA 细胞系研究了剂量依赖性照射对克隆存活、免疫相关细胞表面分子的表达以及对细胞毒性 T 细胞 (CTL) 介导的杀伤的敏感性的影响。克隆形成性以剂量响应方式降低,显示单光子剂量低于 5 Gy 时辐射抗性增强。细胞周期分析显示主要的 G2/M 期停滞,在照射后 12 小时最为明显。多倍体以剂量和时间依赖性方式增加,在 10 Gy 照射后 60 小时达到最大频率。辐射增加了 MHC I 类分子以及免疫检查点分子 PDL-1 和 CD73 的表面表达,特别是在剂量≥ 5 Gy 时,但不增加 MHC II 类分子和 CXCR4 受体的表面表达。细胞毒性测定显示,剂量 ≥ 5 Gy 时 PDA 细胞的 CTL 裂解增加。对于所研究的 PDA 细胞系,我们的数据首次显示单光子剂量 ≥ 5 Gy 有效抑制集落形成并诱导 G2/M 细胞周期停滞。此外,免疫调节细胞表面分子的表达水平发生改变,可能增强肿瘤细胞对 CTL 裂解的敏感性。
更新日期:2020-01-21
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